Dexamethasone increases intracellular cyclic AMP concentration in murine T lymphocyte cell lines

Baus, Erika; Laethem, François Van; Andris, Fabienne; Rolin, Sylvie; Urbain, Jacques; Léo, Oberdan

doi:10.1016/s0039-128x(00)00137-9

Cited by 16 publications

(14 citation statements)

References 40 publications

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“…The CS can increase cAMP accumulation in various cell types in vitro (Hege Thoresen et al, 1989;Yingling et al, 1994;Baus et al, 2001). Our results confirmed this phenomenon in vivo and showed its time pattern.…”

Section: Discussionsupporting

confidence: 81%

“…Our results confirmed this phenomenon in vivo and showed its time pattern. The cAMP elevation by dexamethasone was abolished by the steroid antagonist RU486 or protein synthesis inhibitor cycloheximide (Baus et al, 2001), indicating that it required GR binding and was protein synthesis-dependent. Several mechanisms have been proposed concerning CS effect on cAMP, including increased formation, decreased degradation, as well as regulation of Gs protein.…”

Section: Discussionmentioning

confidence: 99%

“…Several mechanisms have been proposed concerning CS effect on cAMP, including increased formation, decreased degradation, as well as regulation of Gs protein. Baus et al (2001) reported that dexamethasone-induced cAMP correlated with both an increase in adenylyl cyclase activity (cAMP-producing enzyme) and a decrease in phosphodiesterase activity (cAMP-degradation enzyme). However, Christoffersen et al (1984) found dexamethasone decreased phosphodiesterase activity, with no significant effect on adenylyl cyclase.…”

Section: Discussionmentioning

confidence: 99%

“…CSs are known to cause homologous down-regulation of their own receptors via decreased transcription, which subsequently results in decreased mRNA levels and free GR densities in the cytosol (Oakley and Cidlowski, 1993). The CS can also induce adenylyl cyclase and suppress phosphodiesterase based on similar transcriptional control (Baus et al, 2001). Adenylyl cyclase catalyzes the conversion of ATP to cAMP, which is degraded by phosphodiesterase (Butcher et al, 1968).…”

Section: Pharmacokinetic/pharmacodynamic Modelmentioning

confidence: 99%

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Receptor/Gene-Mediated Pharmacodynamic Effects of Methylprednisolone on Phosphoenolpyruvate Carboxykinase Regulation in Rat Liver

Jin

DuBois²,

Almon³

et al. 2004

J Pharmacol Exp Ther

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Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme for gluconeogenesis. To investigate underlying mechanisms of corticosteroid (CS) action in regulating glucose, temporal patterns of hepatic PEPCK gene expression, enzyme activity, and cAMP content were examined in adrenalectomized rats receiving acute and chronic methylprednisolone (MPL) treatments. After single MPL intravenous doses, PEPCK mRNA showed a fast increase, reaching a maximum at around 0.75 h, which was followed by an immediate decline to below baseline after 4 h, an apparent acute tolerance/rebound phenomenon. However, PEPCK enzyme showed continuous hyperactivity for over 72 h. This may be the result of generation of cAMP, an important inducer of PEPCK activity, which peaked at around 6 h. During 7-day subcutaneous infusion of MPL, PEPCK mRNA showed profiles consistent with single-dose results, whereas PEPCK activity increased to a comparable maximum followed by a slow decline. However, the extent of cAMP induction was markedly higher during infusion, which could be attributed to amplification of cAMP synthesis and/or a stabilizing effect of MPL on cAMP degradation. A pharmacokinetic/ pharmacodynamic model was developed based on receptor/ gene mechanisms of CS action. It successfully described the dual effects of MPL on regulating PEPCK message and the post-transcriptional control by cAMP. Our results exemplify the importance of the extent and duration of steroid exposure in mediating pharmacological effects. The model provides quantitation of multiple controlling factors regulating PEPCK and presents insights into its function in glucose metabolism.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pharmacokinetic/pharmacodynamic Modelmentioning

confidence: 99%

See 2 more Smart Citations

Receptor/Gene-Mediated Pharmacodynamic Effects of Methylprednisolone on Phosphoenolpyruvate Carboxykinase Regulation in Rat Liver

Jin

DuBois²,

Almon³

et al. 2004

J Pharmacol Exp Ther

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“…It has been shown that MEFs stimulate tumor progression and release S100A4 into the cell culture medium in vitro (12,20). T-cell monolayer invasion assays (26) showed that T lymphocytes failed to invade into S100A4 −/− MEF monolayer, whereas S100A4 +/+ MEFs strongly attracted T lymphocytes. Moreover, S100A4 antibodies blocked T lymphocyte invasion into the S100A4 +/+ MEF monolayer (Fig.…”

Section: S100a4 Deficiency Suppresses Metastases Of Mammary Tumors Ofmentioning

confidence: 99%

Lung Metastasis Fails in MMTV-PyMT Oncomice Lacking S100A4 Due to a T-Cell Deficiency in Primary Tumors

et al. 2010

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Interactions between tumor and stroma cells are essential for the progression of cancer from its initial growth at a primary site to its metastasis to distant organs. The metastasis-stimulating protein S100A4 exerts its function as a stroma cell-derived factor. Genetic depletion of S100A4 significantly reduced the metastatic burden in lungs of PyMT-induced mammary tumors. In S100A4 +/+ PyMT mice, massive leukocyte infiltration at the site of the growing tumor at the stage of malignant transition was associated with increased concentration of extracellular S100A4 in the tumor microenvironment. In contrast, in S100A4 −/− PyMT tumors, a significant suppression of T-cell infiltration was documented at the transition period. In vitro, the S100A4 protein mediated the attraction of T cells. Moreover, S100A4 +/+ , but not S100A4, fibroblasts stimulated the invasion of T lymphocytes into fibroblast monolayers. In vivo, the presence of S100A4 +/+ , but not S100A4 −/− , fibroblasts significantly stimulated the attraction of T lymphocytes to the site of the growing tumor. Increased levels of T cells were also observed in the premetastatic lungs of tumor-bearing mice primed to metastasize by S100A4 +/+ fibroblasts. Treatment of T cells with the S100A4 protein stimulated production of cytokines, particularly granulocyte colony-stimulating factor and eotaxin-2. The same cytokines were detected in the fluid of S100A4 +/+ PyMT tumors at the transition period. We suggest that release of S100A4 in the primary tumor stimulates infiltration of T cells and activates secretion of cytokines, thus triggering sequential events that fuel tumor cells to metastasize. Similar processes could occur in the premetastatic lungs, facilitating generation of inflammatory milieu favorable for metastasis formation. Cancer Res; 70(3); 936-47. ©2010 AACR.

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Effect of adrenaline and glucocorticoids on monocyte cAMP-specific phosphodiesterase (PDE4) in a monocytic cell line

2002

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An increase in phosphodiesterase 4 (PDE4) in blood mononuclear white cells of patients with atopic dermatitis (AD) has been described. This and other skin disorders worsen during stress, during which there are increased circulating levels of adrenaline and glucocorticoids. The aim of this study was to analyse the effect of both these hormones on PDE4 in inflammatory cells. The human monocyte cell line U-937 was used as a model of blood mononuclear leucocytes. For this purpose, (1) the effect of adrenaline on PDE4 activity was determined, (2) the receptor mediating adrenaline actions was characterized, (3) the role of intracellular cAMP in PDE4 activation was investigated and (4) the effect of glucocorticoids on PDE4 activity was also ascertained. Adrenaline at a concentration of 1 micro M produced a two- to threefold selective increase in PDE4 activity in U-937 cells after 4 h of incubation with the hormone. This stimulation was reversible, as well as concentration- and time-dependent. Cycloheximide (10 micro M) induced a blockade of adrenaline-induced stimulation of PDE4. The stimulatory effect was inhibited by propranolol, but not by atenolol or phentolamine, in a concentration-dependent manner and was mimicked by salbutamol. The stimulation of PDE4 was paralleled by an increase in intracellular levels of cAMP. 8-Br-cAMP and forskolin also increased PDE4 activity. After 4 h of incubation in the presence of adrenaline, inhibition of cAMP degradation by rolipram further increased cAMP levels by about 300% and also enhanced PDE4 activity. These results suggest that adrenaline-induced stimulation of PDE4 is mediated by the beta(2)-adrenoceptor and is related to intracellular levels of cAMP, which might trigger expression and synthesis of the enzyme. The synthetic glucocorticoid dexamethasone (in the concentration range 10(-8) to 10(-6) M) showed no effect on PDE4 activity or on the cAMP accumulation induced by adrenaline, even after prolonged (24 h) incubation with the cells. Of the two stress hormones assayed, PDE4 activity was shown to be sensitive to adrenaline elevation but resistant to changes in glucocorticoid levels in the U-937 monocytic cell line.

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Dexamethasone increases intracellular cyclic AMP concentration in murine T lymphocyte cell lines

Cited by 16 publications

References 40 publications

Receptor/Gene-Mediated Pharmacodynamic Effects of Methylprednisolone on Phosphoenolpyruvate Carboxykinase Regulation in Rat Liver

Receptor/Gene-Mediated Pharmacodynamic Effects of Methylprednisolone on Phosphoenolpyruvate Carboxykinase Regulation in Rat Liver

Lung Metastasis Fails in MMTV-PyMT Oncomice Lacking S100A4 Due to a T-Cell Deficiency in Primary Tumors

Effect of adrenaline and glucocorticoids on monocyte cAMP-specific phosphodiesterase (PDE4) in a monocytic cell line

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